The adipokine leptin is released in proportion to the size of body fat stores and is a key contributor to the control of food intake and maintenance of metabolic homeostasis in normal weight animals and humans. A failure to fully activate leptin signaling proteins results in leptin resistance, which is a predisposing factor for obesity. Approximately 34% of US adults and 17% of children are obese and consumption of sugar sweetened beverages has been implicated in this epidemic of obesity. Rats consuming 30% sucrose solution develop peripheral and central leptin resistance faster than those fed formulated high-fat or high-sucrose diets. Leptin resistance is traditionally associated with a failure increase phosphorylation of the transcription factor signal transducer and activator of transcription 3 (pSTAT3) in areas of the brain that control food intake and energy expenditure. In leptin resistant sucrose-drinking rats basal hypothalamic pSTAT3 is increased and leptin does not increase pSTAT3 or inhibit food intake. Preliminary in vivo and in vitro data provide compelling evidence that increased glucose availability increases activity of the hexosamine biosynthetic pathway (HBP), increases pSTAT3 and causes leptin resistance. HBP activity results in O-GlcNAc modification of hundreds of proteins including enzymes and transcription factors. Basal HBP activity is crucial for many regulatory cell processes, but chronic activation disrupts signaling cascades and promotes cancer, cardiovascular disease and insulin resistance. Rats drink sucrose throughout the day and we hypothesize that the resultant surges in blood glucose chronically activate the HBP and inhibit leptin signaling due to O-GlcNAc modification of the key leptin signaling protein STAT3. Three Specific Aims will test this hypothesis. The first Aim will test whether consumption of liquid sucrose results in repeated excursions of blood glucose that stimulate the HBP, promote protein O-GlcNAc modification and cause leptin resistance. The second Aim will use in vitro studies to investigate the mechanism by which activation of the HBP modifies STAT3 phosphorylation and interferes with leptin signaling. The third Aim will use in vivo rodent studies to test the physiologic impact of HBP activation in the hypothalamus on leptin responsiveness. These Aims will provide significant new information on a mechanism that links consumption of sweetened beverages with increased risk for obesity.